PuSH - Publikationsserver des Helmholtz Zentrums München

Märkl, F.* ; Schultheiß, C.* ; Ali, M.* ; Chen, S.S.* ; Zintchenko, M.* ; Egli, L.* ; Mietz, J.* ; Chijioke, O.* ; Paschold, L.* ; Spajic, S.* ; Holtermann, A.* ; Dörr, J.* ; Stock, S.* ; Zingg, A.* ; Läubli, H.* ; Piseddu, I.* ; Anz, D.* ; Minden, M.D.* ; Zhang, T.* ; Nerreter, T.* ; Hudecek, M.* ; Minguet, S.* ; Chiorazzi, N.* ; Kobold, S. ; Binder, M.*

Mutation-specific CAR T cells as precision therapy for IGLV3-21R110 expressing high-risk chronic lymphocytic leukemia.

Nat. Commun. 15:993 (2024)
Verlagsversion DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
The concept of precision cell therapy targeting tumor-specific mutations is appealing but requires surface-exposed neoepitopes, which is a rarity in cancer. B cell receptors (BCR) of mature lymphoid malignancies are exceptional in that they harbor tumor-specific-stereotyped sequences in the form of point mutations that drive self-engagement of the BCR and autologous signaling. Here, we use a BCR light chain neoepitope defined by a characteristic point mutation (IGLV3-21R110) for selective targeting of a poor-risk subset of chronic lymphocytic leukemia (CLL) with chimeric antigen receptor (CAR) T cells. We develop murine and humanized CAR constructs expressed in T cells from healthy donors and CLL patients that eradicate IGLV3-21R110 expressing cell lines and primary CLL cells, but neither cells expressing the non-pathogenic IGLV3-21G110 light chain nor polyclonal healthy B cells. In vivo experiments confirm epitope-selective cytolysis in xenograft models in female mice using engrafted IGLV3-21R110 expressing cell lines or primary CLL cells. We further demonstrate in two humanized mouse models lack of cytotoxicity towards human B cells. These data provide the basis for advanced approaches of resistance-preventive and biomarker-guided cellular targeting of functionally relevant lymphoma driver mutations sparing normal B cells.
Altmetric
Weitere Metriken?
[➜Einloggen]
Zusatzinfos bearbeiten [➜Einloggen]
Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter Chimeric Antigen Receptors; Xenograft Models; Light-chains; Immunoglobulin; Cll; Immunotherapy; Remissions; Transgene; Vectors; Driven
ISSN (print) / ISBN 2041-1723
e-ISSN 2041-1723
Zeitschrift Nature Communications
Quellenangaben Band: 15, Heft: 1, Seiten: , Artikelnummer: 993 Supplement: ,
Verlag Nature Publishing Group
Verlagsort London
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Unit for Clinical Pharmacology (KKG-EKLiP)
Förderungen Fritz-Bender-Stiftung
SFB-TRR 338/1
Monika-Kutzner-Stiftung
Deutsche Jose Carreras Leukamie-Stiftung
Wilhelm-Sander-Stiftung
Else-Kroner-Fresenius-Stiftung (IOLIN)
German Cancer Aid (AvantCAR.de)
Marie-Sklodowska-Curie Program Training Network for Optimizing Adoptive T Cell Therapy of Cancer - H2020 Program of the European Union
Melanoma Research Alliance Grants
International Doctoral Program iTarget: Immunotargeting of Cancer - Elite Network of Bavaria
Intramural Roux program funding
DFG
LMU Munich's Institutional Strategy LMUexcellent

Bruno und Helene Joster Foundation
European Research Council
Bavarian Research Foundation (BAYCELLATOR)
Bundesministerium fur Bildung und Forschung Projects Oncoattract, CONTRACT and Beyondantibody
FOR2799
Deutsche Forschungsgemeinschaft (DFG)